Diphenylsulphone derivative



Patented Aug. 31, 1943 UNITED STATES PATENT OFFICE- DIPHENYLSULPHONE DERIVATIVE Paul Piihls, Wuppertal-Elberfeld, Germany, as-

signor to Winthrop Chemical Company, Inc., New York, N. Y., a corporation of New York No Drawing. Application September 13, 1940, Se-

rial No. 356,654. 1939 6 Claims.

This invention relates to diphenylsulphone derivatives.

4,4-diamino-diphenylsu1phone and certain derivatives thereof have a favorable influence on the streptococci infections of the Warm-blooded individuals. These compounds are, however, not suitable for injection purposes since they themselves are practically insoluble in water and since their mineral acid salts because of a low basicity of the base react acid to congo and, therefore, cause necrosis upon subcutaneous injection.

In the copending application Ser. No. 274,228, filed May 17, 1939, now U. S. Patent 2,297,024 diphenylsulphone derivatives which are readily soluble in water with neutral reaction and, therefore, are suitable for injection purposes and 'which still have a high activity on the streptococci infections have been described; said diphenylsulphone derivatives contain in the 4- and 4'- positions bound, for instance, by carbamide groups, organic radicals bearing on their part, if desired in the form of their salts with bases, groups rendering the products soluble in water with neutral reaction.

In accordance with the present invention, diphenylsulphone derivatives which likewise are soluble in water with neutral reaction and still have an improved activity, are obtainable by the manufacture of diphenylsulphone derivatives which contain in the 4-position a nitro-, aminoor acylamino-group and in the 4'-position a urea-group, a nitrogen atom of which is connected with an organic radical rendering the diphenylsulphone compound soluble in water by the presence of at least one water-solubilizing group. The said organic radical may be an aliphatic, aromatic and/or heterocyclic radical. The watersolubilizing group contained in this radical may be a carboxylic-, sulphonicor sulphinic acid such usual acid radicals. The afore-mentioned compounds containing an acid group are preferably used in the form of their salts with inorganic or organic bases for injection purposes. Suitable salts are, for instance, the sodium-, ammonium-, calcium-, diethylamine-, ethanolamine-, diethanolamine-, piperidine-, ethylenediamine-, iperazine and similarsalts. The new In Germany September 4,

wherein X stands for a nitrogenous group such as the nitro, amino and acylamino groups, and R stands for the organic radical rendering the products soluble in water such as the radicals of ali phatic polyhydroxy compounds derived from sugars and of aikyl carboxylic, sulphonic and sulphinic acids and aromatic and heterocyclic carboxylic, sulphonic and sulphinic acids including the benzoylarnino-substituted aromatic and heterocyclic carboxylic, sulphonic and sulphinic acids, a ring carbon atom of the benzoyl radical of which is attached to the carbamide nitrogen.

In accordance with the present invention, the said new compounds are obtained by reacting an isocyanate or an urethane of a 4-nitro-4'-aminodiphenylsulphone or of a 4-acylaminoy-aminodiphenylsulphone with an organic compound containing apart from an amino group at least one water-solubilizing group; or vice-versa an isocyanate or a urethane of an organic com pound containing the water-solubilizing group, if desired in the form of an ester derivative, may be reacted with a 4-nitro-4-amino-diphenylsulphone or with a 4-acylamino-4 -amino-diphenylsulphone. The urethane aryl esters, i. e. carbamic acid aryl esters, are preferably used as the urethane compounds referred to above.

The new compounds are also obtainable by oxidizing diphenylsulphides or diphenylsulphoxides which are substituted in the 4-position by a nitro-, aminoor acylamino group and in the 4- position by a urea group, the one nitrogen atom of which is connected with the above specified organic radical having a water-solubilizing group, to the above characterized diphenylsulphone derivatives by the action of an oxidizing agent such as hydrogen peroxide or permanganate.

The said new products furthermore have been obtained by introducing a water-solubiiizing group according to the methods usual for this purpose into an organic radical which is connect ed by means of the urea group with the 4-position of a 4nitro-, 4-aminoor -acylamino-diphenylsulphone. The said groups may be introduced directly or by converting groups which are present in the said organic radical and which can be converted into carboxylic-, sulphonic-, sulphinicor hydroxyl groups according to the methods known per se. Thus, for instance, carboxylic ester, -amide or -nitrile groups or sulphonic acid ester groups or acyloxy groups may be saponified or methyl, aldehyde or mercapto group may be oxidized to the carboxylic or sulphonic acid group.

The 4-amino-diphenylsulphone compounds of the kind above specified may be further obtained by reducing a nitroor azo group standing in the 4'-p0sition of the diphenylsulphone, the 4'- position of which is connected by means of the urea group with the said water-solubilizing organic radical, or azomethine or acylamino groups standing in the 4-position of diphenylsulphone compounds as mentioned before may be converted into the corresponding 4-amino compounds by saponification.

lihe invention is furthermore illustrated by the following examples, without being restricted thereto:

Example 1 36 grams of 4-nitrol'-[N-(3,5"-dicarbomethoxy-phenyl) carbamido] -diphenylsulphone are saponified with alcoholic sodium hydroxide solution The dicarboxylic aci (22.5 grams), obtained after acidifying, decomposes at 225-226 C. It has the following formula:

@NHC oNHGSOl-ONOZ Example 2 grams of 4-acetylamino-4 [N'-(3,5"-dicarbomethoxy phenyl) carbamidol diph'enylsulphone are boiled with alcoholic sodium hydroxide solution (10%) for 1 minute under reflux. After acidifying 32.5 grams of the di'carboxylic acid, decomposing at 23l233 C-., are obtained. The product has the following formula:

I Q-NELC ONE-OSOZO-NHC 0.0m

HOOC

The starting. material is obtained as follows: 29 grams of l-acetylaniinme-amino-diphenylsulphone are boiled under reflux for 3 hourswith 23.5, grams of 1 isocyanatebenzene3,5-dicarboxylio acid methylester in 300 001118. of, acetone. The condensation product is sucked off in the cold, washed with ether and dried at 100 C. 40 grams melting at 240 C. are obtained.

Example 3 27.8 grams of 4-nitro-4'-aminodiphenylsulphone are dissolved in 100 come. of diox'ane, 12.5 grams of dimethylaniline are added and 16 grams of chloroformic acid phenylester are slowly dropped while stirring. After heating for half an hour on the Waterbath, 26.3 grams of 2 naphthylamine-6-sulphonic acid, dissolved in 40.0 cc'ms. of 1% sodium hydroxide solution, are added thereto. The solution is standardized'to a pH of 7.5 by the addition of primarysodium phosphate and boiled for 4 hours under reflux While stirring. The 4-nitro-diphenylsu1phonecarbamic acid phenylester dissolves thereupon. The reaction solution is. made slightly alkaline and the dimethylaniline is blown off with'steain.

After acidifying with glacial acetic acid the ile n01 is removed with steam and the clear red solution is cooled with ice. The condensation product precipitates as a yellow, crystalline precipitate. It is sucked off and dried in the air. The product has the following formula:

Example 4 Example 5 29-grams of 4-amino4i.-acetylamino-diphenyh sulphone are suspended in coins. of dioxane. 12.5 grams of dimethylaniline are added and. 16 grams of chloroformic acid pheny-lester are dropped thereto while stirringf Ifihe temperature rises to almost 70 and the leamino l acet ylaniino-diphenylsulphone is dissolved. After further heating for half an hour on the waterbath, 26.3 grams of, Z-naphthyIamine-B-sulphonic acid, dissolved. in e00 come. of a 1% sodium hydroxide solution, are added thereto and the solution isstandardized toa pH of 7.5. After 5 hours boiling and. stirring the precipitated 4'- acetylamino diphenylsulphone (4;) carbamic acid phenylester has dissolved. The, clear solution is freed from dimethyla-nilin andphenol as described in Examplev 3 and poured ilnto 1000 ccms. of 35% sodium chloride solution whilestirring. The condensation product precipitated thereupon is suckedofi and dried; in the-air. The product has the following formula;

NaOeS 'phenylsulphone and benzo'ylchloride in acetonepyridine and reduction of-tlie *i-'nitro-l"-henzoylamino-diphenyls'ulphone formed melting at 226- C.

In the sanienianner'the l-ainino-fl isoheggoylam n heny sn nhq i Obta ned by h atin 'isohexylicacld'chloride with 4-amino-4-nitrodiphenylsulphone in the presence of pyridine and by reduction of the nitro compound formed.

Instead of the chloroiormic acid phenylester,

the chloroformic acid-fi-naphthylester (boiling at 158 C. under 15 mms. pressure), for instance,

may be used for producing the carbamic acid arylester compounds. The .carbamic acid B- naphthylesters thus formed react slowly with the aminocompounds, while splitting off c-naphthol and forming the urea derivatives of the sulphone. compounds.

Example 6 24.5 grams of 4-acetylamino-4-[N-(6-carbomethoxynaphthyl-2") -carbamido] diphenylsulphone are boiled with 200 ccms. of alcohol, 20 ccms. of 28% sodium hydroxide solution and 20 ccms. of water for 1 minute. By acidifying with hydrochloric acid the carboxylic acid formed precipitates as a white precipitate which is sucked off, washed with water and dried at It melts at 280-281 C. with decomposition. The product has the following formula:

(ID-N300.NHO-sorO-Nncoorn The starting product is obtained as follows:

18 grams of naphthyl-2-isocyanate-6-carboxylic acid methylester are boiled with 23 grams of 4 acetylamino-4-amino diphenylsulphone in 250 ccms. of acetone for hours under reflux. The condensation product is sucked off in the cold, washed with ether and dried at 100 C. It melts at 230 C. with decomposition.

HOOC

Example 7 grams of 4-nitro-4-[N-carboethoxymethyl-carbamido]-diphenylsulphone are subjected to saponification with a 10% alcoholic sodium hydroxide solution for a short time. The carboxylic acid formed is precipitated with dilute hydrochloric acid, sucked 01f, washed with water and dried at 100 C. It has the followin formula:

no 0 c .omNrro ormQsm-Orro:

20 grams. of 4-nitro-4-[N'-(4"-sulphofluoride-phenyl) -ca-rbamido] -diphenylsulphone are saponified with alcoholic sodium hydroxide solution (10%). The clear solution is added to a 35% sodium chloride solution while stirring whereupon the sodium salt of the corresponding sulphonic acid precipitates. formula NaOzSO-NELC ONE-OSOONO:

The starting product is obtained as follows: 27.8 grams of 4-amino-4'-nitro-diphenylsulphone are boiled for one hour with 20.1 grams of phenylisocyanate-4-sulphofluoride in 300 ccms. of acetone. The condensation product is sucked off in the cold. washed with ether and dried at It has the following C. The phenylisocyanate-i'-sulphofluoride has been prepared as follows:

117 grams of p-acetylamino-benzenesulphochloride are treated with 1000 ccms. of water and 35 grams of sodiumfluorlde for 3 hours at 40-45 C. while stirring. The p-acetylaminobenzenesulphofluoride thus obtained is sucked 01f and washed with water. Then it is dissolved in acetone and the solution is dried with potassium carbonate. After evaporation of the acetone, 53 grams of p-acetylamino-benzenesulphofluoride melting at 156-15750. are obtained. 53 grams of this product are boiled with 200 ccms. of dilute hydrochloric. acid under reflux. The solution is filteredwhile hot and the 4-aminobenzenesulphofluoride is precipitated with sodium acetate. The base is dissolved in ether and the solution is dried with potassium carbonate. After evaporation of the ether the 4-aminobenzenesulphofluoride melting at 72-'73 C. is obtained. 60 grams of this product are dissolved in .500 ccms. of benzene. Phosgene is introduced into this solution at usual temperature while stirring. Thereupon the hydrochloric acid salt of the p-aminobenzene-sulphofluoride precipitates. Phosgene is still introduced under reflux while stirring until the hydrochloric acid salt has disappeared and an almost clear solution has been formed. The excess phosgen is removed by introducingair. The benzene solution is filtered and concentrated under reduced pressure. The residue, the phenylisocyanate-4-sulphofluoride, distils at 132 C. under 11 mms. pressure.

Example 9 10 grams of 4-nitro-4'-[Ncarboxymethylcarbamido]-diphenylsulphide are treated with ccms. of glacial acetic acid and 50 ccms. of a 25% aqueous hydrogen peroxide solution for 15 hours at normal temperature while stirring. The 4 nitro-4'-[N'-carboxy methyl carbamidol -diphenylsulphone formed is sucked off, washed with water and dried at 100 C. It melts at 205-208 C. with decomposition. The product has the following formula:

HO 0 C.CH.NH.C omaOsoQ-nm The starting material is obtained as follows:

49.2 grams of 4-nitro-4-aminodiphenylsulphide are boiled under reflux in 400 ccms. 'of acetone with 26 grams of isocyanate-acetic ester for 2 hours. After cooling the crystallized 4-nitro- 4' [N'r-oarbethoxymethyl-carbamido] -dipheny1- sulphide is sucked off, washed with ether and dried at 100 C. It melts at 201-202" C. 58.5 grams of this ester are boiled under reflux with 150 ccms. of 10% alcoholic sodium hydroxide solution, 150 ccms. of alcohol and 50 ccms. of water for 1 minute. The undissolved particles are filtered ofi from the red solution and the filtrate is acidified with dilute hydrochloric acid. The separated yellow acid, the 4-nitro-4-[N-carboxymethyl-carbamido] -diphenylsulphide, is sucked off, washed with water and dried at 100 C. It melts at 171 C. with decomposition.

Example 10 25 grams of 4-carbamido-4'- [N -carboxymethyl-carbamido]-diphenylsulphide are treated with 200 ccms. of glacial acetic acid and 100 ccms. of 25% aqueous hydrogenperoxide solution for 15 hours at usual temperature while stirring. The 4- carbamido-4 [N -canboxy methyl carbamido] diphenylsulphone formed is sucked oiT, washed the compound begins. lowing formula: I

stirring and under reflux.

with water'and dried'at 100 0. Itmelts'above 260 C.; from 250C. agradual-'dark-coloringof The product has the fol- The starting materialis obtained as f ollows 1 51.8 grams" of 4 carbamido-4---amino-diphenylsulphide-are boiled under reflux for-2 hours with 26grams of isocyanateaceticester 1 200 ccms. of acetone. The 4-carbamido-42-lNf- (carbethoxy-methyl)----carbamido] diphenylsulphide crystallizes already while stillvvar'rn.- "It is sucked off after cooling, washed with ether and dried at 100 C. It melts above 260- CZ; from 250 C. a gradual dark-coloring begins.-

62.5 grams of this ester are boiled witlr 150 ccms. of 10% alcoholic sodium hydronide-sclu tion, 150 ccms. of alcohol and- 50 ccms. of water for 2 minutes under reflux. The difiicultlysoluble sodium salt of the 4-carbamido-4-[N carboxymetliyl carbamidol diphenylsulphideis sucked ofi", washed with alcohol and d-riedat 100 C. It is soluble in hot water.

The bamido] -diphenylsulphide is obtained from-the sodium salt by the action ofhydroch loric acid. The melting point is not characteristic same: as inthe case of the ester.

Example 11 15.2 grams of methylglucamine-are dissolved in 200 ccms. of water. 32 grams of l acetylaminodiphenylsulphone-lcarbamic acid phenylester and 150 ccms. of dioxa'ne are added thereto. The

droxy-hexyl) -N' methylcarbamidol diphenylsulphone dissolves readilypin water. The product has the following formula:

In the same the 4-propionylaminmdiphenylsulphonei-carbamic acid phenylester, the '-methoxy-acetylamino-diphenylsulpltone- 4'-carbamic acid phenylestenand the4-carhamido-diphenylsulphone-4 -carbamic acid phenylester are reacted with methylglucamine to the corresponding urea compounds.

Example 12 29.1 grams of 4-carbarnido-4"-an1inodiphenylsulphone are suspended in 100 cents. of-di'o-xane.

12.5 grams of dimethylani-line are added and-l6 grams of chloroiormic acid phenylester, diluted With acetone, are dropped thereto while stirring. The 4 carbamido 4 aminodiphenylsulphone gradually dissolves.- After 1 hours-heating to 80 C. a hot solution of Z-naphthylamine-G=sul-.

phonic acid in iifiO ccms; of water and 4- grams of sodium hydroxide are added. The mixture-- is standardized to a pl-l of- 7 .5 byadding primary sodium phosphate-and boiled for 4 hours-while 4-carbamido-4' EN -caiooxymethyl-'car- The glass- 1 e -carbamido-diasasgwo phenylsulphone-4'-carbamic acid phenylester is dissolved thereupon. The solution is rendered weakly alkaline andthe dimethyl-aniline is blown off with steam. The clear solution is strongly concentrated under reduced pressure. After cooling the precipitated 4-carbamido-4- [N' (2- sodium naphthalene-6! -sulphonate) carbamidol diphenylsulphoneis sucked off and dissolved-in methanol. The methylalcoholic solution: is evaporated underreduced pressure. The remaining urea compound dissolves readily in cold water. It has the following formula:

The 4 carbamidorl'-amino-diphenylsulphone employed as starting material is obtained by reacting potassium-cyanate upon 4-amino-4'-nitrodiphenylsulphidein glacial acetic acid in'the presence-of concentrated hydrochloric'acid, oxidation of the 4-carbamido-4nitrodiphen lsulphide formed melting at 205 C. in glacial acetic acid with hydrogenperoxide and reduction of the 4-carbamido-4-nitrodiphenylsulphone melting at 225 C. I

In the same manner, the 4-carbomethoxyamino-4 -ami-no diphenylsulphone is transformed over the 4-carloamicacid phenylester with 2- naphthylamineefi-sulphonic acid into the corresponding urea compound. The l-carbomethox amino-4-aminodiphenylsulphone employed as starting material and melting. at 235 C. is obtained as follows:

4-arnino-4.-nitrodiphenylsulphide is converted in acetone solution in the presence of pyridine by means of chloroformic acid methylester into the 4- carbomethoxyamino-4 -nitrodiphenylsulphide melting at 157 0., the latter, oxidized in glacial acetic acid with hydrogenperoxide to the4-carbomethoxyamino- 4 nitrodiphenylsulphone, melting at 225 C.; and the nitro-group ofthis compound reduced to the amino group.

Example 13 44.4 grams of mono-sodium salt of the 2-(3- aminobenzoyl -amino) -naphthalene 3,6- disulphonic. acid are dissolved in 300 ccms. of water While adding 4;grams of sodiumhydroxide. 41 grams of' 4-acetylamino-diphenylsulphone 4- carbamic acid phenylester; and 200 coins. otdioxaneare added thereto. The-mixture is standardized to a pHof 7.5 and boiled under reflux while stirring. Afterfi hours boilinga small test portion OI" this mixture givesno longer a precipitate when diluted with Water. The clear solution'isfiltered while hot with animal charcoal and the filtrate is added after cooling to 2.35% sodium chloride solutionwhile stirring. Thereupon, the (ii-sodium salt of the sulphone-({N- phenyll-acetamide}:{2- [3'--(4" phe-nylcarba mido) benzamidol naphthalene disulphonic acid-(3.6) precipitates. It is dissolved in methanol. The methylalcoholic solution is filtered from undissolved sodium chloride and evaporated to dryness. It has the following formula O-Nao 0 .NH

| memo 0 NaOsS I SO3Na so? NH'C O'CH:

The; 2-(3'-aminolcenzoyl).-aminonaphthalene 3,6-disulphnic acid employed as starting material is obtained as follows:

36.5 grams of the mono-sodium salt of the 2-naphthylamine3,G-disulphonic acid are dissolved in 250 ccms. of water containing 4 grams of sodium hydroxide. 30 grams of sodiumacetate are added thereto and, at a temperature of 30-35 C., 36.5 grams of m-nitro-benzoylchloride are introduced while stirring. After a short time, the sodium salt of the 2- (3'-nitrobenzoylamino) naphthalene-3,6-disulphonic acid crystallizes. It is sucked cfi, dissolved in hot water and this solution is dropped into a boiling mixture of 500 grams of iron, 1000 ccms. of water and 10 ccms. of glacial acetic acid while stirring. After 5 hours boiling, the reaction mixture is made alkaline with sodium carbonate, filtered with animal charcoal while hot and the filtrate is mixed with a large quantity of hydrochloric acid after cooling. Thereupon, the 2-(3'-aminobenzoylamino)-naphthalene-3,6-sulphonic acid precipitates in crystals. It is sucked off and dried at 100 C.

In the same manner, the 2-(4'-aminobenzoylamino)-naphthalene-3,6-disulphonic acid, the 2- (4'-aminobenzoylamino) naphthalene-6,8-disulphonic acid, the 1-(4-aminobenzoylamino)- naphthalene-3,8-disulphonic acid and the 2-01- aminobenzoylamine)-6-sulphonic acid are produced and reacted with 4-acetylamino-diphenylsulphone-4'-carbamic acid phenylester to the corresponding sulphone compounds.

I claim:

1. A diphenylsulphone compound of the formula wherein X stands for a nitrogenous group selected from the group consisting of nitro, amino and carboxylic acylamino groups and n stands for one of the numbers 1 and 2, and its alkali and alkaline earth metal, ammonium and amine salts which are soluble in water with neutral reaction.

2. A diphenylsulphone compound of the formula wherein X stands for a carboxylic acylamino group and n stands for one of the numbers 1 and 2 and its alkali and alkaline earth metal, ammonium and amine salts which are soluble in water with neutral reaction.

3. A diphenylsulphone compound of the formula HOOC NH.C ONE-O-SOrO-NO,

and its salts.

4. A diphenylsulphone compound of the formula masonrrOswO-rrm and its salts.

5. A diphenylsulphone compound of the formula NELC O .NE

Boss SOIH SOz-ONHC 0 OH:

and its salts.

PAUL POHLS. 

